Microbial pathogens have long been implicated as environmental insults which might contribute to the development and/or severity of Multiple Sclerosis, a disease of the central nervous system. However concerns with this hypothesis remain. The first concern is that there has not been a clear demonstration that any particular microbial pathogen can directly cause this disease in patients. This has lead to the speculation that the development of Multiple Sclerosis into a clinical disease might require multiple factors including genetic predisposition, as well as exposure to environmental factors like infectious diseases. In fact, it has been suggested that pathogens may not cause Multiple Sclerosis directly, but rather lead to the exacerbation of clinical disease into one of the various forms of Multiple Sclerosis. A second concern with this "pathogen-induced exacerbation" hypothesis is that there is no clear mechanism as to how any particular pathogen might augment developing disease. A variety of mechanisms have been suggested for pathogen-induced activation of encephalitogenic CD4+ T lymphocytes, including molecular mimicry, bystander activation, and epitope spreading. There is evidence to support each of these mechanisms, and there may be more than one involved in the exacerbation of clinical disease. Clearly, if the "pathogen-induced exacerbation" hypothesis is correct, this will be an extremely difficult one to prove using human subjects alone. Using a mouse model of Experimental Autoimmune Encephalomyelitis, we propose to explore one possible mechanism which might contribute to the "pathogen-induced exacerbation" hypothesis of this autoimmune disease. Specifically, we will question whether an autoimmune response against crystallin alpha-beta following an infection might contribute to the exacerbation of clinical disease in this animal model of multiple sclerosis. To perform these studies, we will rely on in vitro and in vivo assays to determine if cells such as macrophages, dendritic cells, and B lymphocytes might serve as professional antigen presenting cells for autoantigens. The presence of auto-reactive CD4+ T lymphocytes will also be determined in the peripheral tissues and in the central nervous system. At the conclusion of these studies, we will have clearly demonstrated the plausibility of the "pathogen-induced crystallin alpha-beta" hypothesis of exacerbated disease in an animal model of Multiple Sclerosis. PUBLIC HEALTH RELEVANCE: Using a mouse model of Experimental Autoimmune Encephalomyelitis, we propose to explore one possible mechanism which might contribute to the "pathogen-induced exacerbation" hypothesis of this autoimmune disease. Specifically, we will question whether an autoimmune response against crystallin alpha-beta following an infection might contribute to the exacerbation of clinical disease in this animal model of multiple sclerosis.